Ciliary proteins specify the cell inflammatory response by tuning NFκB signalling, independently of primary cilia.

Complex inflammatory signalling cascades define the response to tissue injury but also control development and homeostasis, limiting these pathways as therapeutic targets. Primary cilia are sub-cellular regulators of cellular signalling, controlling how signalling is organized, encoded and, in some instances, driving or influencing pathogenesis. Our previous research revealed that disruption of ciliary intraflagellar transport (IFT), altered the cell response to IL-1β, supporting a putative link emerging between cilia and inflammation. Here, we show that IFT88 depletion affects specific cytokine-regulated behaviors, changing cytosolic NFκB translocation dynamics, but leaving MAPK unaffected. RNAseq analysis indicates IFT88 regulates one third of the genome-wide targets, including the pro-inflammatory genes Nos2, Il6 and Tnf. By microscopy, we find altered NFκB dynamics are independent to assembly of a ciliary axoneme. Indeed, depletion of IFT88 inhibits the inflammatory responses in the non-ciliated macrophage. We propose ciliary proteins, including IFT88, KIF3A, TTBK2 and NPHP4, act outside of the ciliary axoneme, to tune cytoplasmic NFκB signalling, and specify the downstream cell response. This is thus a non-canonical function for ciliary proteins in shaping cellular inflammation.